Stress-specific 14-3-3-client modules in digestive cancers: an evidence-graded review of adaptive survival and...

Area of Science:

• Molecular Biology
• Oncology
• Cellular Stress Response

Background:

• 14-3-3 proteins are crucial adaptors regulating cellular processes under stress.
• Dysregulation of 14-3-3 interactions is implicated in various cancers.
• Understanding specific 14-3-3-client modules is vital for cancer research.

Purpose of the Study:

• To review and synthesize stress-specific 14-3-3 protein-client interactions in major gastrointestinal cancers.
• To classify these modules based on mechanistic and clinical evidence.
• To highlight the clinical relevance of specific complexes over total protein expression.

Main Methods:

• Narrative review of existing literature.
• Classification of 14-3-3-client modules based on mechanistic evidence, functional perturbation, client mapping, treatment-state validation, and clinical association.
• Synthesis of findings across gastric, colorectal, pancreatic, and hepatobiliary cancers.

Main Results:

• Identified distinct stress-specific 14-3-3-client modules in gastric, colorectal, and pancreatic cancers.
• In gastric cancer, 14-3-3ζ-G3BP1 retains Bax, inhibiting apoptosis.
• In colorectal cancer, 14-3-3σ-SFN sustains unfolded protein response and chemoresistance.
• In pancreatic cancer, 14-3-3σ-SFN promotes gemcitabine resistance via YAP1 and ribonucleotide reductase.
• Hepatobiliary cancer modules show context-dependent anoikis resistance.

Conclusions:

• Clinically relevant units are stress-specific 14-3-3-client complexes, not overall 14-3-3 expression levels.
• These specific modules play significant roles in cancer progression and treatment response.
• Targeting these defined modules offers potential therapeutic strategies in gastrointestinal cancers.